1. Field of the Invention
The present invention relates to fields of peptide and peptoid chemistry, molecular biology and cell biology. More particularly, the present invention relates to peptidomimetics that antagonize the VEGF receptor and inhibit angiogenesis as well as methods with which to identify said antagonists. In particular, such inhibitors may find use in the treatment of diseases such as cancer and macular degeneration.
2. Description of Related Art
Monoclonal antibodies that antagonize the formation of various hormone receptor interactions are used widely in the clinic. For example, Remicade, and Adalimumab are anti-arthritic antibodies that block binding of Tumor Necrosis Factor (TNF)-α to its cognate receptor and thus reduce inflammation (Taylor, 2003). Avastin (Gerber and Ferrara, 2005), a Vascular Endothelial Growth Factor (VEGF)-binding antibody, prevents VEGF from docking with VEGF Receptor 2 (VEGFR2) (Hicklin and Ellis, 2005), a key step in the angiogenic cascade (Folkman, 1990) that is critical to support solid tumor survival and proliferation (Dvorak, 2002; Millauer et al., 1993; Zeng et al., 2001). Avastin is employed widely in the treatment of various tumors (Hurwitz et al., 2004; Johnson et al., 2004) and, more recently, to block blood vessel formation in “wet” macular degeneration (Ambresin and Mantel, 2007). While therapeutic monoclonal antibodies are obviously of great value, they are not without drawbacks. They are relatively difficult and expensive to manufacture in large quantities, there is some problem with immune reactions (Stevenson, 2005), though this has been minimized by humanization (Mateo et al., 2000).
Thus, it would be of great interest to develop relatively small, easily manipulable synthetic compounds that display antibody-like affinity and specificity for a given receptor, but which could be made cheaply and be easily tailored to carry cargo of various sorts. Unfortunately, it has traditionally proven difficult to isolate small molecule antagonists of protein-protein interactions, particularly those involving large, shallow interaction surfaces typical of hormone receptor complexes (Whitty and Kumaravel, 2006). While many examples are known of small molecules that act as agonists or antagonists of integral membrane receptors, these generally act by alternative mechanisms, for example as inhibitors of the ligand-activated kinase activity of the receptor (Cabebe and Wakelee, 2006; Ciardiello et al., 2003; Thomas, 2003). On the other hand, there are several examples of receptor- or hormone-binding peptide antagonists (D'Andrea et al., 2006). This is not surprising, since peptides are much better able to mimic the natural binding partner of a hormone or receptor than is a classical small molecule. In a few cases, these peptide antagonists have been developed into clinically useful compounds (Liu et al., 2007) but this approach to drug development is severely limited by the sensitivity of peptides to proteolysis. However, there remains a need in the field to develop agents that are able to antagonize those proteins involved with angiogenesis, particularly in the context of pathologic conditions that require the development of new blood vessels.